Object of the present invention are chiral diphosphines, complexes between said diphosphines and transition metals, and their utilization as chiral catalysts in stereoselective (stereocontrolled) reactions, such as, for instance, diastereo- and enantioselective reduction reactions in general, or asymmetric isomerization in general.
Another object of the present invention is a process for the preparation of said chiral diphosphines, as well as a process for the preparation of said chiral complexes and their utilization as catalysts in diasteareo- and enantioselective reactions.
Further another object of the present invention are stereoselective processes, in particular diastereo- and enantioselective reductions in general, which utilize said chiral catalysts.
As is known, stereoselective reactions, in particular the reactions of stereocontrolled reduction, such as, for instance, diastereo- and enatioselective hydrogenations, are of great importance and have been studied for a long time, in fact, such reactions lead directly to the formation of optically active compounds which would be obtainable otherwise only as racemates, with the ensuing need of a subsequent separation of the enantiomers and the related drawbacks which sometimes are found in performing such separation, with the associated high probability of failing to obtain the pure enantiomeric forms; besides, in these cases a further drawback may arise from the presence of an unwished enantiomer, which must be reconverted or disposed of.
In general, the stereocontrolled reduction reactions realized by means of chiral catalysts allow to obtain the optically active reaction products, often also with good enantiomeric excesses.
For instance, the first enantioselective hydrogenation reaction of unsaturated compounds was carried out through the utilization of metal catalysts deposited on chiral supports and goes back to the thirties. Afterwards, homogeneous asymmetric hydrogenation reactions have been studied and described that had been realized by means of special chiral catalysts, constituted by complexes between transition metals and chiral phosphines which acts as ligands-towards the metal.
The literature reports on different types of chiral phosphines which can act as ligands and form chiral complexes with transition metals, such as, for instance, Ruthenium (Ru), Rhodium (Rh), Palladium (Pd), Iridium (Ir) and Platinum (Pt). In particular, chiral phosphines are characterized by one or two stereogenic atoms of phosphorus, which will have, in this case, three different substituents, such as, for instance, DIPAMP which (R,R) enantiomer has the following formula: 
[KNOWLES W. S. et al., J. Chem. Soc. Chem. Commun. 10 (1972); VINEYARD B. D. et al., J. Am. Chem. Soc. 99, 5946(1977)]; phosphines are also described whose chirality is due to the presence of carbon-based stereocentres, such as for instance the compound known as CHIRAPHOS, which (S,S) enantiomer has the following formula: 
[FRYZUK M. D. et al. J. Am. Chem. Soc. 99, 6262 (1977)]; also phosphines are reported whose chirality is due to the presence of an atropisomeric biaryl system, i.e., a system in which the rotation around the simple bond connecting two aryl groups is prevented. For example, WO 92/16536 discloses new racemic and optically active diphosphines, or chiral diphosphines, having a biphenyl structure. Said chiral phosphines are described as ligands in the preparation of complexes with group VIII metals, which complexes are useful as catalysts for asymmetrical hydrogenations and for enantioselective hydrogen shifts in prochiral allylic systems. The chirality of the described phosphines is due to the presence of the biphenyl structure which also renders the corresponding complexes suitable for being used as chiral catalysts.
EP 643065 also discloses a new diphosphine useful as catalyst for asymmetrical hydrogenations; the disclosed diphosphine is characterized by the presence of a biphenyl structure which is responsible for the chirality of the system.
Other diphosphines of this type are for instance BINAP, BIPHEMP or BICHEP, which (R) enantiomers have the following formulae: 
[NOYORI R. et al. J. Am. Chem. Soc. 102, 7932(1980); SCHMID R. et al. Helv. Chim. Acta 71, 897(1988); MIYASHITA A. et al. Chem. Lett. 1849(1989)].
At present, for instance, the catalysts for the stereocontrolled reduction, such as the diastereo- and enantioselective hydrogenation of carbonyl groups, which allow to obtain the best diastereomeric and enantiomeric excesses of secondary chiral alcohols, are those constituted by complexes between transition metals and chiral diphosphines by atropisomery, and in particular complexes between Ru and BINAP.
Of course, the main problem is that of the synthesis of the chiral diphosphine which acts as ligand. In the aforementioned cases, the process of synthesis of the chiral diphosphine is rather complicated, as it involves numerous steps, besides, the diphosphine which is obtained as a racemate needs a laborious resolution process, with low yields and very high costs. As a consequence, the chiral catalyst obtained by formation of a complex between the chiral diphosphine and a transition metal may be very expensive.
An aim of the present invention is to provide a chiral diphosphine suitable for acting as a ligand for transition metals through the formation of particularly stable coordination bonds.
Another aim of the invention is to provide a chiral diphosphine such as to be obtainable more easily from the synthetic point of view compared to the known art. Still another aim of the invention is to provide a process for the preparation of a chiral diphosphine suitable to act as a ligand for transition metals, consisting of simple steps, having contained costs and being industrially applicable.
Still a further aim of the present invention is to provide a new chiral catalyst to be used in stereocontrolled synthesis reactions.
Another aim of the invention is to provide a chiral catalyst to be used in stereocontrolled synthesis reactions, such as to be highly reactive and provided with a high regio-, chemo-, diastereo-, enantio-selectivity.
Still a further aim of the present invention is to provide a chiral catalyst to be used in stereocontrolled synthesis reactions, such as to allow to operate in mild reaction conditions, obtaining anyway high reaction rates.
Another aim of the invention is to allow the realization of stereocontrolled reactions, in particular reduction reactions or isomerization reactions involving the utilization of a chiral catalyst and leading to the formation of optically active products with high diastereomeric or enantiomeric excesses.
These and still other aims and associated advantages which will be more clearly expounded in the following description, are reached by a chiral diphosphine constituted by an aromatic pentatomic biheterocyclic system.
More particularly, said chiral diphosphine constituted by an aromatic pentatomic biheterocyclic system has the following general formula: 
where:
R2 is chosen among hydrogen, phenyl, aryl, linear, branched, cyclic alkyl C1-C10, COOR3, where R3 is linear, branched, cyclic alkyl C1-C10;
Y is chosen among phenyl, substituted phenyl, aryl, substituted aryl, linear, branched, cyclic alkyl C3-C10;
R1 is chosen among phenyl, substituted phenyl, aryl, substituted aryl, linear, branched, cyclic alkyl C1-C10, OR5, where R5 is linear, branched, cyclic alkyl C1-C10, or
each pentatomic heterocyclic aromatic ring of said system is condensated to a substituted or unsubstituted benzene or naphthalene ring, according to the following formula: 
where n ranges from 0 to 6, R2 may also be equal to zero, R4 is chosen among hydrogen, linear, branched, cyclic, substituted or unsubstituted alkyl C1-C10.
The aforementioned graphic representation is to be construed as being non limitative, meaning that, for instance, each of said pentatomic heterocyclic aromatic rings is condensed to said substituted or unsubstituted benzene or naphthalene ring also according to the following formula: 
where R4, n, R2 are defined as above.
The aromatic pentatomic biheterocyclic system is chosen among:
1,1xe2x80x2-bipyrrole, 2,2xe2x80x2-bipyrrole, 3,3xe2x80x2-bipyrrole
3,3xe2x80x2-bithiophenee
3,3xe2x80x2-bifuran
1,1xe2x80x2-biimidazole
and the corresponding benzocondensed (II A) (II B), (V A) (V B),
4,4xe2x80x2-bipyazole, 5,5xe2x80x2-bipyrazole
1,1xe2x80x2-1,3,4-triazole
4,4xe2x80x2-biisoaxazole
4,4xe2x80x2-biisothiazole
5,5xe2x80x2-biimidazole
3,3-bibenzothiophenes
3,3xe2x80x2-bibenzofurans,
2,2xe2x80x2-biindoles
1,1xe2x80x2-bibenzoimidazoles.
The chiral dihosphines having the following formulae: 
proved to be particularly advantageous according to the present invention.
Also the chiral diphosphine having the following formula: 
proved to be particularly advantageous, always according to the present invention.
Also the chiral diphosphines having the following formula: 
proved to be particularly advantageous, always according to the invention.
In another embodiment, the present invention is directed to a chiral diphosphine comprising an aromatic pentatomic biheterocyclic system according to the following general formula: 
where X is C or N; W is C or N; and with the proviso that only one of X or W is N;
where:
R2 is selected from the group consisting of hydrogen, phenyl, aryl, linear, branched, or cyclic alkyl C1-C10, COOR3, where R3 is linear, branched, or cyclic alkyl C1-C10;
Y is selected from the group consisting of phenyl, substituted phenyl where substituents are selected from the group consisting of linear, branched, or cyclic alkyl C1-C10, halogen, OR6 where
R6 is linear, branched, or cyclic alkyl C1-C10, aryl, substituted aryl where substituents are selected from the group consisting of linear, branched, or cyclic alkyl C1-C10, halogen, OR6 where R6 is linear, branched or cyclic alkyl C1-C10, linear, branched or cyclic alkyl C3-C10;
R1 is selected from the group consisting of phenyl, substituted phenyl where substituents are selected from the group consisting of linear, branched, or cyclic alkyl C1-C10, halogen, OR6 where R6 is linear, branched, or cyclic alkyl C1-C10, aryl, substituted aryl where substituents are selected from the group consisting of linear, branched, or cyclic alkyl C1-C10, halogen, OR6 where R6 is linear, branched, or cyclic alkyl C1-C10, linear, branched, or cyclic alkyl C1-C10, OR5, where R5 is linear, branched, or cyclic alkyl C1-C10, or
each pentatomic heterocyclic aromatic ring of said system is optionally fused to an optionally substituted benzene or naphthalene ring, wherein the optional substituents are selected from the group consisting of linear, branched, or cyclic alkyl C1-C10, halogen, OR6 where R6 is linear, branched, or cyclic alkyl C1-C10, or unsubstituted according to the following formula: 
or according to the following formula: 
where X is N; and
where R4 is selected from the group consisting of hydrogen, linear, branched, cyclic, or unsubstituted alkyl C1-C10, n ranges from 0 to 6; where R2 is selected from the group consisting of hydrogen, phenyl, aryl, linear, branched or cyclic alkyl C1-C10, COOR3 where R3 is linear, branched, or cyclic C1-10.
In another embodiment the present invention provides a chiral catalyst for stereocontrolled synthesis comprising a complex between a transitional metal and a chiral diphosphine constituted by an aromatic pentatomic biheterocyclic system where said chiral diphosphine is constituted by an aromatic pentatomic biheterocyclic system selected from the group consisting of
1,1xe2x80x2-bipyrrole, 2,2xe2x80x2-bipyrrole, 3,3xe2x80x2-bipyrrole
1,1xe2x80x2-biimidazole,
5,5xe2x80x2-biimidazole,
4,4xe2x80x2-bipyrazole, 5,5xe2x80x2-bipyrazole,
1,1xe2x80x2-bi-1,3,4-triazole,
2,2xe2x80x2-biindoles, and
1,1xe2x80x2-bibenzoimidazoles.
In particular, the chirality of said diphosphines (I A) (I B), (II A) (II B), (V A) (V B) is due to the presence of the pentatomic aromatic biheterocyclic system, which is a C2 symmetry atropisomeric system, i.e. characterized by a high rotatory barrier around the bond connecting the two heterocyclic systems [Eliel; Stereochemistry of Carbon Compounds, Int.Stud.Edition McGraw Hillxe2x80x94Tokyo 1962xe2x80x94p. 156 foll.].
Besides, said diphosphines according to the present invention are characterized in that the heterocyclic system, when it is electron-rich, increases the electronic availability of the phosphorus atom. Thanks to these characteristics, the diphosphines according to this invention are advantageously utilized as chiral ligands in the preparation of complexes with transition metals in which the coordination bond with the metal is helped precisely thanks to the electronic availability of the ligand, lended to the phosphorus atom by the heterocyclic system; such complexes are in their turn utilized as chiral catalysts in stereocontrolled syntheses, in particular in the diastereo- and enantioselective reduction reactions, such as for instance the hydrogenation reactions.
Always according to the present invention, said chiral diphosphines are prepared according to a process consisting sting of simple steps.
Always according to the invention and solely by way of example, a general process for the preparation of a chiral diphosphine having the general formula (I A) (I B) is schematically expounded. Said process comprises the following steps:
synthesis of the pentatomic aromatic biheterocyclic system through oxidative coupling of the corresponding pentatomic heterocyclic anion;
formation of the di-anion of the biheterocyclic system;
reaction of said di-anion with P(Y)2Cl or Po(Y)2Cl, where Y is chosen among phenyl, substituted phenyl, aryl, substituted aryl, linear, branched, cyclic alkyl C3-C10, obtaining the racemic diphosphine (I A)+(I B) or the racemic diphosphinoxide;
conversion of said racemic diphosphine (I A)+(I B) into the corresponding racemic diphosphinoxide by oxidation reaction according to known techniques;
reaction of said racemic diphosphinoxide with an acid chiral resolving agent, obtaining two diasteroisomeric adducts;
separation of said diastereomeric adducts by fractional crystallization;
basic treatment of each of said two separated diastereomeric adducts, to give the corresponding enantiomerically pure diphosphinoxides;
reduction of said enantiomerically pure diphosphinoxides with known reducing agents, such as, for instance, silanes, to give said enantiomerically pure chiral diphosphines (I A) and (I B).
Obviously, the aromatic biheterocyclic system may be prepared also according to other techniques known to the technicians of this sector. Besides, said formation of the di-anion of the biheterocyclic system may happen, in case of nitrogenated heterocyclic rings, also on the nitrogen atom.
More particularly, always according to this invention, said racemic diphosphine (I A)+(I B) may be advantageously directly resolved by column chromatography with the use of chiral means, such as the stationary phase, the eluent system and the like.
Still said acid chiral resolving agent is preferably chosen, for instance among dibenzoyltartaric acid, ditoluyltartaric acid, camphorsulphonic acids and the like.
As said already, the chiral diphosphines according to the present invention are utilized as ligands for the complexation of transition metals, in particular the metals of the VIII group, such as for instance Ru, Rh, Pd, Pt, Ir, to form chiral complexes which act as catalysts in stereocontrolled reactions.
According to the invention, said complexes between the chiral ligand and the metal are preferably obtained by an exchange reaction between the chiral diphosphine and a complex of the chosen metal, in which the bond between metal and ligand must be more labile than the bond that will form between metal and diphosphine, in this way, the diphosphine will substitute for the ligand in the coordination to the metal, forming a preferred coordination bond. In particular, in the above exchange reaction, the metal is utilized in coordination with ligands such as for instance 1,5-cis,cis-cycloctadiene, norbornadiene, (ethylene)2, triarylstibine, benzonitrile and the like.
In particular, the complex constitiuted by the chosen metal and the ligand is dissolved in a suitable solvent and then the chiral diphosphine is added, either in the solid state or dissolved in its turn in a suitable solvent; the progress of the reaction and hence the formation of the chiral complex, is followed through the examination of possible colour changes, as well as by means of spectroscopic methods, for instance by 31P-NMR, and GC. At the end of the reaction, the solvent is eliminated and the chiral complex formed may be utilized as it is or it may be subjected to a further purification according to known techniques.
The solvents preferably utilized for the preparation of the chiral complex are, for instance, chlorinated solvents, alcohols, aromatic hydrocarbons (toluene), ethers, dimethylformamide. The above chiral complexes are preferably prepared at the time when they are used as catalysts in stereocontrolled reactions.
Always according to the present invention, the chiral catalysts constituted by complexes between the chiral diphosphine and transition metals turn out to be more selective compared to those utilized in the known art; in fact, the geometry of the diphosphine ligand according to this invention may determine different bonds lengths and bond angles compared to those of the known traditional ligands, and consequently the stereoelective reactions which utilize said chiral catalysts provide advantages such as a remarkable reaction rate, mild reaction conditions, for instance as it concerns pressure and temperature conditions and the quantity of catalyst utilized, as well as the possibility of using solvents having a lower ecological impact.
Besides, said chiral catalysts have a high chemo-, enantio- and diastereo-selectivity and are advantageously utilized to perform stereocontrolled reactions, in particular diastereo- and enantioselective reduction reactions, such as, for instance, reduction of olefins (xe2x80x94Cxe2x95x90Cxe2x80x94), reduction of ketone carbonyl groups (xe2x80x94Cxe2x95x90O), reduction of imine groups (xe2x80x94Cxe2x95x90Nxe2x80x94), reduction of enamines (xe2x80x94Nxe2x80x94Cxe2x95x90Cxe2x80x94), obtaining optically active compounds with high diastereomeric and enantiomeric excesses.
Always according to the present invention, said chiral catalysts are utilized to carry out hydroformylation reactions, hydrocyanation reactions and double bond isomerization reactions. By way of non limitative example of this invention, the preparation of some chiral diphosphines (III R) (III S), (IV R) (IV S), (VI R) (VI S), (VII R) (VII S), (VIII R) (VIII S), the preparation of some chiral complexes between said diphosphines and the metals Ru and Rh respectively, as well as the utilization of said complexes as chiral catalysts according to this invention are described as follows, for instance; their utilization in the reduction of ethyl 3-oxo-butyrate, methyl 2-oxocyclopentane-carboxylate, xcex1-acetamidocinammic acid and other ones.